The long range goal of this proposal is to begin to understand the regulation of synovial cell proliferation and functional in rheumatoid arthritis. Factors produced in the complex cellular microenvironment of the rheumatoid joint play a central role in the control of cellular proliferation and in the synthesis and release of inflammatory mediators. We propose to study these processes in situ using hybridization histochemistry and in vitro focusing on signal transduction and gene regulation. Synthetic oligonucleotide probes for growth factors (IL-1, TNF, CSFs, PDGF, TGF, IFN), genes associated with proliferation (myc, fos, ODC) and inflammatory mediators (plasminogen activator, collagenase) will be used to identify sites of cellular synthesis in sections of synovial biopsies. The role of the diacy1g1ycerol- protein kinase C pathway in synovial cell responses to specific factors will be determined by direct measurement of diacy1g1ycerol and assessment of phosphoprotein changes in the cells. The expression and mechanism of regulation of the genes encoding c-myc, c-fos, ODC, plasminogen activator and collagenase will be determined in isolated synovial lining cells in response to specific factors. This group of studies may identify novel targets for therapeutic intervention in rheumatoid arthritis.